DOI: 10.1093/annhyg/mef709 Uranium and Pulmonary Inflammatory Response: Study of the Molecular Mechanisms Involved in the Induction of TNFα Secretion by Macrophages

Uranium inhalation can induce, at the lung level, fibrosis and neoplasia. Although it has been demonstrated that these pathologies are associated with inflammation, little is known concerning the pattern of cytokine production after uranium exposure. We then decided to study the effect of uranium on cytokine production by macrophages, as well as the related molecular mechanisms involved. We demonstrated that, contrary to interleukin (IL)-1β, IL-6 and IL-10, a significant and dose-dependent tumour necrosis factor α (TNFα) secretion was induced by uranium, but not by other heavy metals such as gadolinium. TNFα secretion was detected 24 h after uranium addition and depends on the uranium chemical form. Moreover, our results show that uranium can impair the capacity of macrophages to produce normal amounts of TNFα in response to bacterial infection. The TNFα production is regulated at the post-transcriptional level and probably at the transcriptional level, and is mediated through the c-Jun N-terminal kinase and p38 pathways, via the activation of the protein kinase C, as well as through the activation of NF-κB